DOI: 10.1111/jdv.

14673 JEADV

REVIEW ARTICLE

Immune response patterns in non-communicable

inflammatory skin diseases
K. Eyerich,1,* S. Eyerich2
1
Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany
2
ZAUM – Center of Allergy and Environment, Technical University and Helmholtz Center Munich, Munich, Germany
*Correspondence: K. Eyerich. E-mail: kilian.eyerich@tum.de

Abstract
Non-communicable inflammatory skin diseases (ncISD) such as psoriasis or atopic eczema are a major cause of global
disease burden. Due to their impact and complexity, ncISD represent a major challenge of modern medicine. Dermatol-
ogy textbooks describe more than 100 different ncISD based on clinical phenotype and histological architecture. In the
last decades, this historical description was complemented by increasing molecular knowledge – and this knowledge is
now being translated into specific therapeutics. Combining the enormous advances made in lymphocyte immunology
and molecular genetics with clinical and histological phenotyping reveals six immune response patterns of the skin –
type I immune cells cause the lichenoid pattern characterized by immune-mediated cell death of keratinocytes; type II
immune cells underlie the eczematous pattern with impaired epidermal barrier, infection and eosinophils as well as the
bullous pattern with loss of epithelial integrity; Th17 cells and ILC3 mediate the psoriatic pattern characterized by acan-
thosis, high metabolic activity and neutrophils; dysbalance of regulatory T cells causes either the fibrogenic pattern with
rarefication of cells and dermal thickening or the granulomatous pattern defined by formation of granulomas. With more
and more specific therapeutic agents approved, classifying ncISD also according to their immune response pattern will
become highly relevant. This review defines the six immune response patterns of ncISD and highlights therapeutic
strategies targeting key lymphocyte mediators.
Received: 31 August 2017; Accepted: 19 October 2017

Conflicts of interest
None declared.

Funding sources
None declared.

An immunologic view at inflammatory skin
diseases
Non-communicable inflammatory skin diseases (ncISD) are fre-
quent, affected individuals suffer from a devastating loss of qual-
ity of life, and socio-economic costs are enormous. The complex
pathogenesis of ncISD is based on genetic predisposition and
environmental influences that result in impaired epithelial func-
tion and altered immunity. Historically, disease classification in
dermatology relies on precise clinical description in combination
with histological description of microscopic tissue alterations
and infiltrating immune cells. This classification is complex, and
at times misleading. At the same time, insights into mechanisms
how distinct lymphocyte subsets terminally orchestrate the
inflammatory response and how these lymphocytes interact with
resident skin cells1 resulted in a translational revolution leading
to more and more specific therapeutics.2 To acknowledge these
recent advances made in design and approval of specific
immune-mediating therapeutics, a classification of ncISD
according to their immune response patterns is required (Fig. 1,
Tables 1 and 2). This review summarizes what is known about
immunology, histopathology and clinical phenotype for each of
the immune response patterns. It further describes limitations of
the classification, early pathogenic events, and focuses on thera-
peutic consequences and future developments.
Lichenoid pattern (pattern 1)
The major physiologic role of the lichenoid pattern is disposal of
keratinocytes that are potentially infected with intracellular
microbes or are (pre-)carcinogenic due to DNA damages beyond
repair. It is characterized by a cytotoxic immune response
against keratinocytes of the basal layer (‘interface dermatitis’)
that is mediated by killer T cells (Tc1), Th1 cells, ILC1, NKT and

JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
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Immune patterns in ncISD 693

Lichenoid

PATTERN 1
IL-12 IFN-γ
Th1/ TNF-α
ILC1

TBET
Physiological role:
cellular immunity
a) Eczematous
PATTERN 2

IL-4 Th2/ IL-4

ILC2 IL-5
IL-13
b) Blistering
GATA3

Physiological role:
parasites/humoral immunity

Precursor

Th17/ IL-17 Psoriatic

ILC3 IL-21
PATTERN 3

IL-1ß IL-22
IL-6
IL-23 RORc2
TGF-β
IL-22
Th22 TNF-α
IL-6
TNF-α

AHR
Physiological role: a) Fibrogenic
Barrier Homeostasis/
Wound Healing
PATTERN 4

IL-10
iTreg
IL-2 TGF-β b) Granulomatous
TGF-β
FOXP3

Physiological role: limitation

Figure 1 Lymphocyte subsets drive distinct response patterns in the skin. Distinct lymphocyte subgroups differentiate out of common
na€ıve precursor cells under specific micro-environmental stimuli. Lymphocyte subsets are characterized by lineage-defining transcription
factors as well as secreted cytokines. These cytokines elicit six distinct cutaneous response patterns. Shown are representative histologi-
cal and clinical pictures of each response pattern.

JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
 694

JEADV 2018, 32, 692–703

Table 1 Hallmarks of immune response patterns in ncISD

1 2a 2b 3 4a 4b
Lichenoid Eczematous Bullous Psoriatic Fibrogenic Granulomatous
Clinical Polygonal papules, sharply Vesicles, papules, Bullae with surrounding Pustules, thick Skin thickening, epidermal Brownish/ yellowish
phenotype demarcated livid plaques, erythema, erosion, erythema, erosions, desquamation, sharply atrophy, telangiectasia, papules, without
fine and shiny desquamation crusts, desquamation, crusts demarcated plaques papules without desquamation
sebostasis desquamation
Histological Interface dermatitis, Spongiosis, serum Acantholysis/ (micro)-abscess/ neutrophils, Presence of mucin/ amyloid, Presence of
phenotype hypergranulosis, lymphocyte crusts, eosinophils, epidermolysis with regular acanthosis, dilated thickening of fibres, cellular Granulomas, normal or
infiltration till deeper layers, oedema cellular infiltration capillaries rarefication, normal or atrophic epidermis
cytoid bodies atrophic epidermis
Patho-mechanism/ Apoptosis, necroptosis Downregulation of Direct lysis of antibody, Recruitment of neutrophils, Extracellular deposit of Granuloma formation
molecular epithelial innate Opsonization Activation of epithelial innate peptides/ peptidoglycans/
phenotype immunity, immunity, mucins, growth factors
Epithelial barrier Migration of epithelial cells,
impairment, Downregulation of epithelial
Eosinophil recruitment, differentiation,
mast cell activation vascularization
Major cytokines IFN-c IL-4, IL-5, IL-13, IL-31 IL-4, IL-5 IL-17A, IL-17F, IL-21, IL-22 TGF-b, IL-10,
IL-10 TNF-a (non-Treg)
Biomarkers Skin: CXCL10, RIP-3, Fas/ Blood and skin: CCL17, Blood and skin: Specific Blood: HBD-2 Skin: Foxp3, COMP Skin: Adipophilin74
FasL, Caspase 3 CCL22 antibody levels Skin: IL-36, NOS2
Eyerich and Eyerich

© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
 Table 2 ncISD grouped into immune response patterns
1 2a
Lichenoid
Alopecia areata
Ashy dermatosis (Erythema
dyschronicum perstans)
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Benign lichenoid keratosis
Contact dermatitis†, allergic/
photo-allergic/ photo-toxic/
irritant/ systemic
Dermatomyositis
Drug eruption (lichenoid,
fixed)
Erythema multiforme
Graft-vs.-host disease,
lichenoid
Graft-vs.-host disease,
sclerodermatous†
Graham–Little–Piccardi–
Lasseur syndrome
Keratosis lichenoides
chronica†
Lichen nitidus
Lichen striatus
Lichen (planus, planopilaris)
Lichen planus
pemphigoides†
Lupus erythematosus
(discoid, subacute, chilblain,
tumid)
Lymphocytic infiltration
(Jessner-Kanof)
Pityriasis lichenoides et
varioliformis acuta Mucha-
Habermann
Pityriasis lichenoides
chronica
© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
Eczematous
Atopic eczema/ dermatitis
Childhood granulomatous
periorificial dermatitis†
Chronic urticaria (cholinergic,
idiopathic, physical)
Chronic actinic dermatitis
Chronic superficial dermatitis/
small plaque parapsoriasis†
Contact dermatitis†, allergic/
photo-allergic/ photo-toxic/
irritant/ systemic
DRESS syndrome
Dyshidrotic eczema
Drug eruption, spongiotic
Eosinophilic cellulitis (Wells
syndrome)
Eosinophilic annular erythema
Eosinophilic folliculitis (Ofuji)
Erythema toxicum neonatorum
Gianotti-Crosti syndrome
Granuloma gluteale infantum
Ichthyosis, acquired
Lichen simplex chronicus
Nummular eczema/ dermatitis
Patchy pityriasiform lichenoid
eczema
2b
Bullous
Adult linear IgA bullous
dermatosis
Brunsting-Perry cicatricial
pemphigoid
Bullous pemphigoid (IgG, IgE
type)
Chronic bullous dermatosis of
childhood
Cicatricial pemphigoid
Dermatitis herpetiformis
(Duhring)
Epidermolysis bullosa
acquisita
Lichen planus pemphigoides†
Pemphigoid gestationis
(Herpes gestationis)
Pemphigus foliaceus
Pemphigus erythematosus
(Senear-Usher)
Pemphigus herpetiformis
Pemphigus, IgA type
Pemphigoid vegetans
Pemphigus vulgaris
3 4a
Psoriatic
Acne vulgaris
Acne keloidalis (Folliculitis
keloidalis nuchae)
Acne fulminans
Acne inversa (Hidradenitis
suppurativa)
Acrodermatitis continua
suppurativa (Hallopeau)
Acute febrile neutrophilic
dermatosis (Sweet)
Acute generalized
exanthematous pustulosis
Acute generalized pustular
bacterid (Andrews)
Chronic superficial dermatitis/
small plaque parapsoriasis†
Dissecting cellulitis of the scalp
Drug eruption, psoriasiform
Folliculitis decalvans
Impetigo herpetiformis
Infantile acropustulosis
Keratosis lichenoides chronica†
Palmoplantar pustulosis
PAPA syndrome
Pityriasis rubra pilaris
Prurigo pigmentosa†
Fibrogenic
Amyloidosis (Ear amyloid;
nodular)
Atrophoderma (Pierini-Pasini)
Eosinophilic fasciitis (Shulman)
Graft-vs.-host disease,
sclerodermatous†
Lichen amyloidosis
Hyalinosis cutis et mucosae
(Urbach-Wiethe)
Keloid
Lichen myxedematosus
Lichen sclerosus et atrophicus
Morphea/ scleroderma (linear/
profunda)
Mucinosis (acral persistent
popular; popular)
Nephrogenic fibrosing
dermopathy
Parry-Romberg syndrome
Pretibial myxedema
Reticular erythematous
mucinosis (REM)
Scleromyxedema
Striae distensae
Systemic sclerosis
4b
Granulomatous
Actinic granuloma
Annular elastolytic giant cell
granuloma
Cheilitis granulomatosis
(Miescher/ Melkersson-
Immune patterns in ncISD
Rosenthal)
Childhood granulomatous
periorificial dermatitis†
Drug reaction, interstitial
granulomatous
Facial aseptic granuloma
Foreign body granuloma
Granuloma annulare
Interstitial granulomatous
dermatitis
Necrobiosis lipoidica
Palisaded neutrophilic
granulomatous dermatitis
Rosacea†
Sarcoidosis
695
696 Eyerich and Eyerich

NK cells (type 1 lymphocytes). This cytotoxic reaction is driven

by the master regulator of type 1 lymphocytes, IFN-c and cyto-
toxic granules such as granulysin,3 perforin,4 granzyme B5 and
Fas/FasL.6 In line with that observation, transcriptional network
Granulomatous

comparison of lesional lichen planus and lupus erythematosus

with non-interface skin diseases revealed that differentially
expressed genes are attributable to type 1 lymphocytes as well
as to the effect of IFN-c on keratinocytes, including apoptosis
4b

and necroptosis (unpublished data). Furthermore, interface

dermatitis is induced in murine models of xenotransplantation
or adoptive transfer of keratinocyte-reactive cytotoxic T cells.7
In cell culture models, FasL induces the characteristic hyper-
granulosis while IFN-c causes keratinocyte apoptosis with
cytoid body formation, and ICAM-1 expression.8 Increasing
Fibrogenic

evidence suggests an additional and important role for plasma-

cytoid dendritic cells and IFN-a in the pathogenesis of liche-
4a

noid diseases, possibly via recruitment and amplification of

interface dermatitis.9
Psoriasis (plaque type, inverse,

These molecular alterations have direct consequences that can

(palmoplantar, generalized)

be observed histologically: type 1 lymphocytes form a band

along the basal membrane that is called ‘lichenoid infiltrate’.
palmopantar, guttate)
Psoriasis pustulosa

SAPHO syndrome
Reiter’s syndrome

Keratinocytes show signs of cell death, and cytoid bodies are pre-
Sebopsoriasis

sent. Clinically, this results in flattened, polygonal papules with

Rosacea†

shiny desquamation; maximum clinical variants are erosions or

Psoriatic

bullae.
3

Eczematous pattern (pattern 2a)

The major physiologic role of the eczematous pattern is defence
against extracellular parasites. Furthermore, recent evidence sug-
gests a role in protection against toxins.10 Skin lesions are domi-
nated by Th2 and ILC2 cells (type 2 lymphocytes) secreting IL-4,
IL-5, IL-13 and IL-31. These cytokines affect the epidermis in
two ways: IL-4 and IL-13 downregulate genes of the epidermal
Bullous

differentiation complex, thus impairing the epidermal barrier

2b

and resulting in dry skin.11 Furthermore, IL-4 and IL-13 inhibit

cutaneous innate immunity12,13 which explains why most
patients affected by eczematous diseases suffer from skin colo-
Polymorphic light eruption†

Stasis dermatitis (eczema

nization with Staphylococcus aureus or other microbials.14 Th2-

Polymorphic eruption of

Seborrhoeic dermatitis
Prurigo pigmentosa†

†More than one pattern, dominant pattern unresolved.

derived IL-31 also impacts epidermal barrier and is a critical

Perioral dermatitis

Prurigo nodularis

mediator of itch, a leading symptom of most diseases grouped

Zoon’s balanitis
Pityriasis alba
Eczematous

into the eczematous pattern.15,16 IL-5 is a strong activator of

pregnancy

craquele)

eosinophil and basophil granulocytes as well as mast cells.17 The

release of a plethora of mediators from these cells leads to
2a

oedema and influx of further immune cells into the skin.

The type 2 immune deviation results in histological hallmarks
fibrosing alopecia (Kossard)
Polymorphic light eruption†

Toxic epidermal necrolysis

such as spongiosis, serum crusts, and a mixed cellular infiltrate

Postmenopausal frontal
Table 2 Continued

composed of lymphocytes and eosinophil granulocytes in the

acute phase and irregular acanthosis in the chronic phase char-
acterize the eczematous pattern. Clinically, the phenotype
Lichenoid

eczema presents as epidermo-dermatitis with co-occurrence of

Vitiligo

vesicles, papules, erythema, erosions and desquamation as well

1

as dry skin.

JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
Immune patterns in ncISD 697

Bullous pattern (pattern 2b)
A distinct pathology mediated by type 2 lymphocytes results in
the bullous pattern, whose physiologic role is neutralization of
extracellular microbes. Type 2 lymphocytes instruct B cells and
plasma cells to form the antibody subclasses IgE, IgG1 and IgG4
via secretion of IL-4 and IgA via secretion of IL-5. The contribu-
tion of other lymphocytes such as follicular helper T cells to
pathogenic antibody formation in bullous skin diseases is
currently under debate.18 IgG, IgA or IgE19 antibodies directed
against structural proteins of the skin elicit the bullous pattern.
They may either directly lead to keratinocyte apoptosis and loss
of cellular adhesion, a concept called apoptolysis,20 or bind to
their target and cause secondary inflammation via opsoniza-
tion.21
Histological hallmark of type 2 lymphocyte-mediated auto-
antibody formation is destruction of the skin integrity as a result

Pattern
1 2a 2b 3 4a 4b
Atopic Hidradenitis Sclero-
Lupus Lichen Urticaria Pemphigoid Psoriasis Sarcoidosis
Target eczema suppurativa derma

TNF-α

IL-12
n.d. n.d.
(p40/p23)

IL-17 n.d. n.d. n.d. n.d. n.d.

IL-4Ra n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.

IgE n.d. n.d. n.d. n.d.

CD20

TGF-β n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.

bLys n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.

IL-1 n.d. n.d. n.d.

IL-6 n.d. n.d. n.d. n.d. n.d.

Very high efficacy

(>90% improve >90%)
Size: level of evidence

High efficacy Drug approved,

Colour: efficacy

(>75% improve >75%) in clinical use

Good efficacy Double-blind,

(>50% improve >50%) randomized trials exist
Moderate efficacy Case series or
(<50% improve <50%) case reports

No / conflicting evidence/
negative effect

Figure 2 Efficacy of specific therapeutics in index diseases of each immune response pattern. Level of evidence is indicated by size,
level of efficacy by colour of circles.

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on behalf of European Academy of Dermatology and Venereology.
698
of acantholysis, a gap between epidermis and dermis, or dermal
split. An inflammatory infiltrate composed of lymphocytes, eosi-
nophil or neutrophil granulocytes is always observed. Using
immune-fluorescence, antibody deposits of distinct patterns are
disease-defining. Clinically, the primary resulting lesion is a blis-
ter with surrounding erythema; depending on the thickness of
the epidermal roof and manipulation, also erosions and crusts
are frequently observed. Circulating specific antibodies are typi-
cal and represent biomarkers of bullous skin diseases.22 Of note,
diseases of the lichenoid or eczematous pattern may show a bul-
lous clinical variant; those variants are not regarded as bullous
pattern diseases, but rather as maximal variants of interface der-
matitis or spongiosis, respectively, due to their distinct primary
pathology.
Psoriatic pattern (pattern 3)
The psoriatic pattern is mediated by a group of lymphocytes
comprised of Th17, Tc17, ILC3 and Th22 cells (type 3 lympho-
cytes) that share the physiologic role to warrant homeostasis at
barrier organs such as the skin and mucous membranes of lung
and gastrointestinal tract.23 The pattern is caused by increased
epidermal metabolism as well as by activation of innate immune
signals. IL-21 and IL-22 increase keratinocyte proliferation and
migration and inhibit their differentiation, thus contributing to
acanthosis and parakeratosis.24,25 IL-17A and IL-17F induce ker-
atinocyte secretion of several antimicrobial peptides as well as of
CXCL8, a chemokine recruiting neutrophils to the epidermis,
and VEGF that stimulates vascularization.23,26
Collectively, this results in histological hallmarks such as
regular acanthosis with hyperparakeratosis, (micro)-abscesses
in the upper layers of the epidermis, dilated dermal capillar-
ies and a lymphocytic dermal infiltrate. Clinically, a type 3
lymphocyte response is reflected by sharply demarcated pla-
ques with thick desquamation. Sterile pustules are a further
hallmark of the psoriatic pattern. IL-36 proteins and induci-
ble nitric oxidase (NOS2)27 in the skin and the antimicrobial
peptide HBD-2 in the serum28 are valid biomarkers of the
psoriatic pattern.
Fibrogenic pattern (pattern 4a)
The fibrogenic pattern is a consequence of prolonged lympho-
cyte anti-inflammatory activity, usually a counter-regulation of a
preceding inflammatory response. Lead cytokines of causative
regulatory T cells (Tregs) such as iTreg, Th3 and Tr1 (type 4
lymphocytes) are IL-10 and TGF-b. The fibrogenic pattern is
mediated via TGF-b that induces numerous pro-fibrotic genes
in distinct tissue cells.29 Furthermore, it is central in endothelial-
to-mesenchymal transition to pro-fibrotic myofibroblasts.30 The
consequence is excessive extracellular matrix production, depo-
sition and tissue remodelling (fibrosis).
Alterations in the regulatory T-cell department histologically
lead to fibrosis that is observed as thickened collagen bundles
JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
Eyerich and Eyerich
and diminished number of cells. The lymphoid infiltrate is typi-
cally mild and located in deeper skin layers. The epidermis is
normal or atrophic. This is reflected by clinical hallmarks such
as well-demarcated thickening of the whole skin and a shiny,
atrophic epidermis that may be surrounded by erythema in
active lesions.
Granulomatous pattern (pattern 4b)
Granuloma formation is a general mechanism of the immune
system after identification of a potentially harmful molecule that
cannot be eliminated. In the skin, such molecules may be of
infectious nature or degenerated extracellular matrix.31 Recently,
the term ‘Immunocompromised districts’ (ICD) has been pro-
posed for a localized immune dysbalance in the skin after
trauma. Interestingly, granulomatous skin diseases occur fre-
quently in ICD predilection sites.32 As compared to the other
patterns, level of evidence for a dominating role of a single lym-
phocyte subset is low for the granulomatous pattern. Both pro-
inflammatory and regulatory T cells33 are involved. The balance
of TNF-a and type 4 lymphocyte-derived IL-10 expression seems
to be critical for granuloma development and sustainability.34
Interestingly, Tregs decrease after therapy with TNF-a blocking
antibodies, indicating a functional link of Tregs and Th1/Th17
cells via TNF receptor 2.35
The histological architecture of a granuloma is comprised of a
centre of epitheloid cells and histiocytes that may melt to giant
cells or die and leave a cell-free mass (caseating granuloma). This
centre is surrounded by lymphocytes to a varying degree. In the
skin, granulomas develop in the dermis, the epidermis is typi-
cally non-involved or atrophic. Clinically, granulomatous dis-
eases present as brownish papules of sharp demarcation with or
without epidermal desquamation. Figurated or annular manifes-
tation is regularly observed.
Concept limitations
The pattern principle deciphers only inflammatory skin diseases
with a marked interaction of epithelia and inflammatory infil-
trate. This excludes inflammation at deeper layers of the skin
such as panniculitis and vasculitis, and it excludes also primary
dyskeratotic diseases without marked inflammation such as
monogenetic keratinization disorders (ichthyosis), acantholytic
dyskeratosis or keratosis pilaris. Furthermore, the current con-
cept is focused on terminal lymphocyte-mediated molecular
events, because these are shared by different ncISD and they can
be targeted therapeutically. The concept does not integrate the
more heterogeneous early pathogenic events mediated by non-
lymphoid immunity, although innate signals may influence the
clinical course of ncISD. Typical examples are type 1 interferons
that mediate lichenoid diseases36 and psoriasis,37 alterations in
the inflammasome causing autoinflammatory diseases,38 and
Toll-like receptor-induced activation of acute phase proteins
that alter eczematous diseases.39
on behalf of European Academy of Dermatology and Venereology.
Immune patterns in ncISD
Pattern interactions
ncISD are usually dominated by one immune response pattern,
but their complexity and heterogeneity may be reflected by a
mixture of patterns, especially in chronic disease situations.
This holds, for example, true for atopic eczema, where type 2
lymphocytes are causative despite a mixed infiltrate of lympho-
cytes reflected by morphologic changes in the course of the dis-
ease.14 Also contact dermatitis is not exclusively mediated by
type 2 immunity, even though it is clinically and histologically
to be attributed to the eczematous pattern. Other examples are
bullous variants of lichenoid or eczematous diseases or granu-
loma formation that may occur in the course of several ncISD
such as lichen planus, lichen nitidus or lichen striatus. Further-
more, early lichenoid pattern responses may ultimately trans-
form into the fibrogenic pattern, as frequently observed in
scleroderma.
Evidence for the relevance of a lymphocyte subset balance is
given by side-effects observed after therapeutic intervention.
Specific treatment of one lymphocyte subset causing an
immune response pattern might cause imbalance towards
another immune response pattern. The most evident example
is treatment of psoriatic pattern diseases with molecules
inhibiting TNF-a. A side-effect is dryness of the skin and
eosinophilia40 – hallmarks of the eczematous pattern. In gen-
eral, so-called paradoxical effects after treatment with biologics
acting specifically on lymphocyte subsets comprises two phe-
nomena. On the one hand, a spatial shift of lymphocytes, for
example from the gastrointestinal system to the skin, results in
development of psoriasis-like skin inflammation in patients
treated for inflammatory bowel diseases. On the other hand, a
shift in immune response patterns might result in lupus-like,
lichenoid, eczematous or granulomatous cutaneous immune
responses.41
Trigger factors and early events
The concept of lymphocyte-driven inflammatory patterns in the
skin is further supported by insights into the biochemistry of
antigens and mechanisms by which they stimulate lymphocytes.
Although for the majority of ncISD, the primary antigen remains
unknown, recent evidence suggests that different types of anti-
gens exist. A first group consists of common self-antigens in the
skin such as DNA, collagens, antimicrobial peptides and desmo-
somal components. Several of these antigens are proposed to
play a role in psoriasis, namely the antimicrobial peptide LL-
37,42 the melanocytic protease ADAMTSL543 and the phospholi-
pase PLA2G4D.44 Depending on the underlying lymphocyte
reaction, self-antigens cause different immune response patterns.
Desmoglein 3 (Dsg3) may stand exemplary: Dsg3-specific type 2
lymphocytes are causative for pemphigus vulgaris,45 but a type 1
dominated immune response results in interface dermatitis46
and type 3 lymphocytes specific for Dsg3 cause a psoriasis-like
inflammation in mice.47
JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
699
In contrast to self-antigens, exogenous antigens frequently
influence the resulting immune response in the skin. One exam-
ple is birch or grass pollen that carry lipid mediators (PALMs)
inducing a type 2 immune response.48 In line with that observa-
tion, lymphocytes reacting to common aeroallergens in early
patch test reactions are almost exclusively Th2 cells.13 In con-
trast, microbial antigens derived from candida or staphylococci
preferentially induce Th17 cells.49 Guttate psoriasis is induced
by molecular mimicry after infection with streptococci.50 Lichen
planus is associated with HCV infection.51
Lessons learned for specific therapy
The current complex disease classification of ncISD results in
the fact that clinical studies leading to drug approval are under-
taken only in a small minority of diseases, while for most dis-
eases, an off-label use of biologics is common practice.52
Grouping ncISD according to their molecular pathogenesis
gives a rationale for the use of specific therapies (Fig. 2 and
Table 2). One example is the rare disease pityriasis rubra pilaris
(PRP) that is grouped in the psoriatic pattern. Despite missing
approval, biologics used for psoriasis are also effective in
PRP.53 Specific therapeutics targeting type 3 lymphocytes,
more recently type 2 lymphocytes and finally first evidences for
type 1 or type 4 targeting molecules, strengthen the concept of
immune response patterns in the skin.
No satisfying specific therapy is available for lichenoid (pat-
tern 1) skin diseases (Figure 2). Despite the fact that belimumab,
a monoclonal antibody targeting the B lymphocyte stimulator
bLys, is approved for systemic lupus erythematosus,54 efficacy at
cutaneous lesions is limited. Also for lichen planus, established
biologics failed.55 Thus, there is a high unmet medical need to
define cutaneous endpoints in skin autoimmune diseases, and to
identify new therapeutics.56 In line with the pathogenic concept
of the lichenoid pattern, early studies investigating antibodies
targeting either IFN-a or IFN-c are encouraging.57
More advanced are therapeutics targeting type 2 lymphocytes
mediating the eczematous (pattern 2a) and the bullous (pattern
2b) patterns. Dupilumab inhibits effects of IL-4 and IL-13 via
targeting the IL-4 receptor a. Phase III studies in atopic eczema
show a clinical efficacy superior to all previous therapeutic
attempts.58 Neutralizing the IL-4-induced antibody subtype IgE
using omalizumab is an approved and efficient therapy for
chronic urticaria.59 In contrast to type 2-targeted therapies, con-
flicting evidence exists regarding efficacy of TNF inhibitors or
ustekinumab in eczematous diseases. While some case series are
encouraging,12,60 others report lack of long-term evidence61 or
paradoxical eczematous reactions after therapy with TNF inhibi-
tors.62
An established therapy for diseases following the bullous pat-
tern (pattern 2b) is rituximab that eliminates B cells by targeting
CD20.63 Furthermore, it is speculated that blocking of IL-4
might be effective in bullous diseases such as pemphigus.64
on behalf of European Academy of Dermatology and Venereology.
700 Eyerich and Eyerich

Figure 3 Immune response patterns in non-communicable inflammatory skin diseases (ncISD). The pathogenesis of most ncISD is
based on the interaction of lymphocytes and epithelial cells in the skin. Depending on the dominating lymphocyte subset, these interac-
tions might be characterized by cytotoxic events (pattern I: lichenoid); reduced antimicrobial peptides, impaired skin barrier, and eosino-
phils (pattern II: eczematous); antibody deposits and blistering (pattern IIb: bullous); enhanced metabolism and neutrophils (pattern III:
psoriatic); rarefication of cells and deposit of extracellular matrix (pattern IVa: fibrogenic); or granuloma formation (pattern IVb: granuloma-
tous). [Correction added on 09 February after online publication: Figure 3 was missed out in previous version and has been added in this
version].

JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology.
Immune patterns in ncISD
The translational revolution in ncISD started when therapies
specifically inhibiting type 3 lymphocytes and the psoriatic pat-
tern (pattern 3) became available (Figure 2). Today, several anti-
bodies targeting TNF-a (infliximab, adalimumab, golimumab,
etanercept), IL-12p40 (ustekinumab), and IL-17A (secuk-
inumab, ixekizumab) are approved for psoriasis with enormous
clinical efficacy.65 Recently, adalimumab was also approved for
hidradenitis suppurativa (HS).66 Also ustekinumab seems to be
effective in HS.67 A lot of evidence exists for efficacy of type 3
targeting therapies in other diseases grouped in the psoriatic pat-
tern, for example PRP.68
Therapies neutralizing regulatory T cells and with that the fibro-
genic (pattern 4a) or eventually the granulomatous (pattern 4b)
pattern are in early clinical studies. Namely, fresolimumab, an anti-
body targeting TGF-b, had positive effects in a small clinical study
with patients affected by sclerosis.69 Other specific therapies did
not significantly improve skin symptoms in scleroderma, including
a recently published study on tocilizumab, an antibody targeting
IL-670 (Table 2, Figure 3). [Correction added on 09 February
after online publication: the figure citation was previously incorrect
and table citation has been updated in this version]
For the granulomatous reaction pattern, best evidence exists
for therapies targeting TNF-a or IL-12p40. While case series
report conflicting evidence on efficacy,71 TNF-a inhibitors may
also induce granulomas in a paradoxical manner.72 A similar situ-
ation is reported for rituximab.73 Thus, no fully convincing thera-
peutic option to treat granulomatous skin diseases exists to date.
Technological advances drive both a better understanding of
lymphocyte-mediated downstream events in the pathogenesis of
ncISD as well as development of therapeutics specifically inter-
fering with lymphocyte subpopulations. That is why a down-
stream-oriented molecular classification of ncISD as proposed in
this review is reasonable and why the current classification based
on clinical picture and histology needs revision. A challenge of
the future will be to standardize diagnostics of ncISD and to
define adequate endpoints for clinical studies beyond the dis-
eases psoriasis and atopic eczema. Although it may not be obvi-
ous at first glance, grouping ncISD according to their immune
response pattern is the first step towards individualized (also
called precision) medicine. It may be speculated that the future
of defining and treating ncISD will be a combination of the
immune response pattern at disease-level with early pathogenic
triggers at the individual patient’s level. Specifically, an individ-
ual patient will be classified into one of the six immune response
patterns to determine the ideal symptomatic therapy, and in par-
allel specific early events – e.g. environmental trigger factors,
stress, or infections – will be identified to combine the symp-
tomatic therapy with individualized disease prevention.
Acknowledgements
The authors wish to thank Heidrun Behrendt and Johannes Ring
for their critical review of the manuscript. K.E. was supported by
JEADV 2018, 32, 692–703 © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
701
grants of the German Research Foundation (EY07/3-1) and the
European Research Council (IMCIS 676858). S.E. was supported
by the Helmholtz Association.
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